JPWO2006043490A1 - Non-aromatic ring fused pyrimidine derivatives - Google Patents

Abstract

  Provided are a novel pyrimidine derivative or a pharmaceutically acceptable salt thereof fused with a non-aromatic ring selected from dihydrothiophene, dihydrofuran, cycloalkyl and the like, and a pharmaceutical composition containing the compound as an active ingredient. These compounds exhibit excellent insulin secretion promoting action and blood glucose raising action. Therefore, pharmaceutical compositions containing these compounds as active ingredients are based on these actions, such as insulin-dependent diabetes (type 1 diabetes), non-insulin-dependent diabetes (type 2 diabetes), insulin-resistant diseases and obesity. Useful for treatment and / or prevention.

Description

  The present invention relates to a pharmaceutical, particularly a novel non-aromatic ring-fused pyrimidine derivative or a pharmaceutically acceptable salt thereof useful as an insulin secretagogue or a diabetes therapeutic agent, and a pharmaceutical comprising these compounds as active ingredients.

  Diabetes mellitus is a disease whose main feature is chronic hyperglycemia and develops due to an absolute or relative lack of insulin action. In clinical practice, it is roughly classified into insulin-dependent diabetes (hereinafter referred to as “type 1 diabetes”) and non-insulin-dependent diabetes (hereinafter referred to as “type 2 diabetes”). In type 2 diabetes, which accounts for about 90% of diabetic patients, a decrease in insulin secretion from pancreatic β-cells is one of the major causes of the onset, particularly postprandial hyperglycemia due to early insulin secretion disorders. Currently, sulfonylurea (SU agent) is the mainstream as an insulin secretagogue, but is prone to hypoglycemia and is known to cause secondary ineffectiveness due to pancreatic exhaustion in long-term administration. Moreover, although the SU agent is effective for blood glucose control between meals, it is difficult to suppress hyperglycemia after meals. Recently, large-scale clinical trials confirmed that correction of postprandial hyperglycemia is important for diabetic complications and progression inhibition (Non-patent Document 1). In addition, it has been reported that arteriosclerosis develops at the time of only postprandial hyperglycemia, and that the persistence of postprandial mild hyperglycemia increases mortality due to causes such as cardiovascular disease (Non-patent Documents 2 and 3). ). This indicates that postprandial hyperglycemia, even if mild, is an independent risk factor for cardiovascular death. With the above background, the importance and necessity of pharmacotherapy for postprandial hyperglycemia has been recognized. Therefore, a drug having an insulin secretion promoting action has a profile suitable for correcting postprandial hyperglycemia and / or fasting blood glucose, and is considered useful for the treatment and prevention of type 1 diabetes and type 2 diabetes.

  International Publication No. WO 00/31047 (Patent Document 1) discloses a cyclopentane fused pyrimidine derivative as a compound having an effect of increasing the concentration of cyclic guanosine monophosphate (cGMP) by activating soluble guanylate cyclase. Diabetes is exemplified as a disease and pathological condition in which increased cGMP levels are desirable or for which the compounds can be used in therapy and prevention. However, there is no specific disclosure of the compound of the present invention, and no specific data that can be applied to the treatment of diabetes such as insulin secretion promoting action.

  International Publication No. WO 00/46214 (Patent Document 2) discloses a cyclohexane-fused pyrimidine derivative as a compound having an effect of increasing the concentration of cyclic guanosine monophosphate (cGMP) by activating soluble guanylate cyclase. Diabetes is exemplified as a disease and pathological condition in which an increase in cGMP concentration is desirable or for which the compound can be used in therapy and prevention. However, there is no specific disclosure of the compound of the present invention, and no specific data that can be applied to the treatment of diabetes such as insulin secretion promoting action.

  International Publication No. WO 03/049739 (Patent Document 3) discloses condensed pyrimidine derivatives as glycogen synthase kinase-3 (GSK-3) inhibitors, and diseases in which these compounds are useful, namely GSK. Diabetes is exemplified as a disease caused by -3. However, there is no specific disclosure of the compound of the present invention, and no specific data that can be applied to the treatment of diabetes such as insulin secretion promoting action.

  International Publication No. WO 2004/065391 (Patent Document 4) discloses a thiophene-fused pyrimidine derivative substituted with cyano as a phosphodiesterase 7 (PDE 7) inhibitor and is expected to be improved by inhibiting PDE 7 Examples of diseases include type 1 and type 2 diabetes. However, there is no specific disclosure of the compound of the present invention, and no specific data that can be applied to the treatment of diabetes such as insulin secretion promoting action.

  Japanese Patent Application Publication No. 4-224580 (Patent Document 5) discloses a nitrogen-containing ring-fused pyrimidine derivative as a compound having a bactericidal action, but does not specifically disclose the compound of the present invention. Further, there is no description or suggestion that it can be applied to the treatment of diabetes such as insulin secretion promoting action.

  International Publication No. WO 2004/087056 pamphlet (Patent Document 6) discloses a condensed pyrimidine derivative as a transforming growth factor-beta (TGFβ) inhibitor, but there is no specific disclosure of the compound of the present invention. Further, there is no description or suggestion that it can be applied to the treatment of diabetes such as insulin secretion promoting action.

  European Patent Publication EP 0 276 057 (Patent Document 7) discloses sulfur-containing ring-fused pyrimidine derivatives as β-adrenergic blocking agents, but there is no specific disclosure of the compounds of the present invention. Further, there is no description or suggestion that it can be applied to the treatment of diabetes such as insulin secretion promoting action.

  International Publication No. WO 2005/014558 (Patent Document 8) discloses condensed pyrimidine derivatives as ion channel inhibitors, but there is no specific disclosure of the compounds of the present invention. Further, there is no description or suggestion that it can be applied to the treatment of diabetes such as insulin secretion promoting action.

Further, sulfur-containing ring-fused pyrimidine derivatives are known as intermediates for C ₆₀ derivative synthesis (Non-patent Documents 4 and 5).

N. Engl. J. Med., 329: 977-986, 1993 Lancet, 354: 617, 1999 Brit. Med. J., 321: 405-413, 2000 Tetrahedron, 54 (37), 11141-11150, 1998 Tetrahedron Letters, 38 (14), 2557-2560, 1997 International Publication No. WO 00/31047 Pamphlet International Publication No. WO 00/46214 Pamphlet International Publication No. WO 03/049739 Pamphlet International Publication No. WO 2004/065391 Pamphlet Japanese Patent Application Publication No. 4-224580 International Publication No. WO 2004/087056 Pamphlet European Patent Publication EP 0 276 057 International Publication No. WO 2005/014558 Pamphlet

  As described above, since the insulin secretagogue is useful for the treatment and prevention of type 1 diabetes, type 2 diabetes, and insulin resistance disease, creation of a further superior insulin secretagogue is desired.

  The present inventors diligently researched a compound having an insulin secretion promoting action, and found that the non-aromatic ring-fused pyrimidine derivative of the present invention has an excellent insulin secretion promoting action, thereby completing the present invention.

［式中の記号は、以下の意味を示す。
A：
群X¹、群X²、群X³及び群X⁴からなる群より選択される環。なお、この環を構成する炭素原子は、低級アルキル、-O-低級アルキル、ハロゲン、カルボキシル、-CO₂-低級アルキル及びカルバモイルからなる群より選択される1つ以上の基で置換されていてもよい。また、この環を構成する硫黄原子は、酸化されていてもよい。
群X¹：

からなる群。
群X²：

からなる群。
群X³：

からなる群。
群X⁴：

からなる群。
-R¹：
以下の（１）乃至（３）から選択される基。
（１）少なくとも1つのハロゲンで置換されたフェニル。なお、このフェニルはさらに置換基を有していてもよい。
（２）それぞれ置換されていてもよいシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、又はシクロヘプチル。
（３）ピリジル、ピリダジニル、ピリミジニル、ピラジニル、ピロリル、チエニル、チアゾリル、オキサゾリル、イミダゾリル、イソチアゾリル、イソオキサゾリル、ピラゾリル、又は少なくとも1つのハロゲンで置換されているフリル。なお、これらの環は、1つ以上の同一又は異なるハロゲンで置換されていてもよい。また、これらの環は、式（Ｉ）におけるピリミジン環の2位と、これらの環を構成する炭素原子で結合している。
但し、Aが群X⁴から選択される環である場合、-R¹は少なくとも3つのハロゲンで置換されたフェニルを示す。
-R²：
式（ＩＩ）で示される基、又は置換されていてもよい環状アミノ。

［式中の記号は以下の意味を示す。
-R²¹、-R²²：
同一又は異なって、-H、低級アルキル、低級アルケニル、低級アルキニル、シクロアルキル、フェニル、芳香族ヘテロ環、非芳香族ヘテロ環又は-O-低級アルキル。なお、これらの基はそれぞれ置換されていてもよい。］
但し、Aが群X²若しくは群X³から選択される環である場合、-R²は置換されていてもよい環状アミノを示す。
但し、2-(2-フルオロフェニル)-N,N-ジメチル-5,7-ジヒドロチエノ[3,4-d]ピリミジン-4-アミン、及び2-シクロプロピル-4-ピペラジン-1-イル-5,7-ジヒドロチエノ[3,4-d]ピリミジンを除く。］That is, according to the present invention, the fused pyrimidine derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing these compounds as active ingredients, and type 1 diabetes, type 2 diabetes And / or a pharmaceutical composition that is a therapeutic agent for an insulin resistant disease.

[The symbols in the formula have the following meanings.
A:
A ring selected from the group consisting of group X ¹ , group X ² , group X ³ and group X ⁴ . The carbon atom constituting the ring may be substituted with one or more groups selected from the group consisting of lower alkyl, —O-lower alkyl, halogen, carboxyl, —CO ₂ -lower alkyl and carbamoyl. Good. Moreover, the sulfur atom which comprises this ring may be oxidized.
Group X ¹ :

A group consisting of
Group X ² :

A group consisting of
Group X ^3:

A group consisting of
Group X ^4:

A group consisting of
-R ¹ :
A group selected from the following (1) to (3).
(1) Phenyl substituted with at least one halogen. This phenyl may further have a substituent.
(2) Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl each optionally substituted.
(3) Pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, or furyl substituted with at least one halogen. These rings may be substituted with one or more same or different halogens. Further, these rings are bonded to the 2-position of the pyrimidine ring in the formula (I) with the carbon atoms constituting these rings.
Provided that when A is a ring selected from group X ⁴ , —R ¹ represents phenyl substituted with at least three halogens.
-R ² :
A group represented by the formula (II) or a cyclic amino which may be substituted.

[The symbols in the formula have the following meanings.
-R ²¹ , -R ²² :
The same or different, -H, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, phenyl, aromatic heterocycle, non-aromatic heterocycle or -O-lower alkyl; Each of these groups may be substituted. ]
However, when A is a ring selected from Group X ² or Group X ³ , -R ² represents an optionally substituted cyclic amino.
However, 2- (2-fluorophenyl) -N, N-dimethyl-5,7-dihydrothieno [3,4-d] pyrimidin-4-amine and 2-cyclopropyl-4-piperazin-1-yl-5 , 7-Dihydrothieno [3,4-d] pyrimidine is excluded. ]

さらに好ましくは、以下に示される環である。

また、式（Ｉ）におけるR¹として、好ましくは少なくとも１つのハロゲンで置換されたフェニルであり；より好ましくは少なくとも３つのハロゲンで置換されたフェニルである。また、式（Ｉ）におけるR¹の別の態様として、好ましくはそれぞれ置換されていてもよいシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、又はシクロヘプチルであり；より好ましくはそれぞれ置換されていてもよいシクロブチル、又はシクロペンチルであり；さらに好ましくはシクロブチル、又はシクロペンチルである。
また、式（Ｉ）におけるR²として、好ましくは置換されていてもよい環状アミノであり；より好ましくは置換されていてもよいピペラジン、若しくは置換されていてもよいピペリジンであり；さらに好ましくは置換されていてもよいピペリジンである。As A in the formula (I), preferably is a ring selected from the group X ^1; and more preferably ring selected from the group X ¹ sulfur atom constituting the ring is oxidized. Specific examples of the ring selected from the group X ¹ in which the sulfur atom constituting the ring is oxidized include the following rings.

More preferred are the rings shown below.

In addition, R ¹ in formula (I) is preferably phenyl substituted with at least one halogen; more preferably phenyl substituted with at least three halogens. Further, as another embodiment of R ¹ in the formula (I), preferably each is an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more preferably each optionally substituted cyclobutyl Or cyclopentyl; more preferably cyclobutyl or cyclopentyl.
R ² in formula (I) is preferably an optionally substituted cyclic amino; more preferably an optionally substituted piperazine, or an optionally substituted piperidine; more preferably a substituted It may be piperidine.

The condensed pyrimidine derivative represented by the formula (I) is preferably a compound in which A is a ring selected from the group X ¹ (the sulfur atom constituting the ring may be oxidized); A compound wherein A is a ring selected from group X ¹ (the sulfur atom constituting the ring may be oxidized), and R ¹ is phenyl substituted with at least one halogen; More preferably, A is a ring in which A is selected from group X ¹ (the sulfur atom constituting the ring may be oxidized), and R ¹ is phenyl substituted with at least three halogens. Particularly preferably A is a ring selected from group X ¹ (the sulfur atom constituting the ring may be oxidized), R ¹ is phenyl substituted with at least three halogens; ² is an optionally substituted cyclic amino Most preferably, A is a ring selected from group X ¹ (the sulfur atom constituting the ring may be oxidized), and R ¹ is substituted with at least three halogens. A compound that is phenyl and R ² is an optionally substituted piperazine or an optionally substituted piperidine.
As another embodiment of the condensed pyrimidine derivative represented by the formula (I), a compound in which A is preferably a ring selected from group X ¹ (a sulfur atom constituting the ring may be oxidized). More preferably, A is a ring selected from the group X ¹ (the sulfur atom constituting the ring may be oxidized), and R ¹ is each optionally substituted cyclobutyl or cyclopentyl More preferably, A is a ring selected from the group X ¹ (the sulfur atom constituting the ring may be oxidized), and each R ¹ is optionally substituted cyclobutyl Or a compound that is cyclopentyl; particularly preferably, A is a ring selected from group X ¹ (the sulfur atom constituting the ring may be oxidized), and each R ¹ is substituted. Good cyclobutyl, also Is cyclopentyl, a compound in which R ² is an optionally substituted cyclic amino; most preferably a ring wherein A is selected from group X ¹ (the sulfur atom constituting the ring may be oxidized) And R ¹ is a cyclobutyl or cyclopentyl which may be substituted, and R ² is a piperazine which may be substituted or a piperidine which may be substituted.

As the fused pyrimidine derivative represented by the formula (I), particularly preferred compounds are
3- {4- [2- (4-Chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] piperazin-1-yl } Propanamide,
1- [2- (4-Chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] -4- (3-hydroxypropyl Piperidin-4-ol,
N-({1- [2- (4-Chloro-2,5-difluorophenyl-6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] piperidin-4-yl } Methyl) -2-hydroxyacetamide,
3- {1- [2- (4-Chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] piperidin-4-yl } Propanamide,
3-({1- [2- (4-Chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] piperidine-4- Il} amino) propan-1-ol,
3-({1- [2- (4-Chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] piperidine-4- Yl} amino) propionic acid,
4- [1- (2-cyclopentyl-6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl) piperidin-4-yl] butyric acid,
4- [1- (2-cyclobutyl-6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl) piperidin-4-yl] butyric acid, and
4- {1- [2- (4-Chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl) piperidin-4-yl ] Butyric acid,
As well as these pharmaceutically acceptable salts.

The compound of the present invention has an excellent insulin secretion promoting action and an inhibitory action on blood sugar elevation. Therefore, the compound of the present invention represented by the formula (I) is effective for the treatment and / or prevention of type 1 diabetes, type 2 diabetes and / or insulin resistance disease based on the action.
The pharmacological action of the compound of the present invention was confirmed by the following test examples.

(1) Insulin secretion promoting action measurement test In this test, the insulin secretion promoting action of the test compound using the mouse pancreatic β cell line MIN6B1 cells was examined, and glibenclamide having a commercially available insulin secretion promoting action was examined as a control compound. did. The test method is shown below.
MIN6B1 cells were seeded in a 48-well plate at 1 × 10 ⁵ cells / hole (0.25 ml) (the medium was DMEM (Dulbecco's Modified Eagle Medium) containing 25 mM glucose and 10% FCS (fetal calf serum). I used the ones added so as to be). Two days later, the medium was removed with an aspirator, and KRB-HEPES buffer containing 2.8 mM glucose (Krebs-Ringer-bicarbonate-N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid; 130 mM) warmed to 37 ° C. NaCl, 4.7 mM KCl, 1.2 mM KH ₂ PO ₄ , 1.2 mM MgCl ₂ · 6H ₂ O, 0.25 mM CaCl ₂ · 2H ₂ O, 2.5 mM NaHCO ₃ , 0.5% BSA, 10 mM N-2-hydroxyethylpiperazine This was washed four times with 0.2 ml of N'-2-ethanesulfonic acid (pH 7.4), and again with 0.2 ml of the same buffer, and incubated at 37 ° C. for 30 to 60 minutes. The above buffer solution was removed with an aspirator, and KRB-HEPES containing 16.8 mM glucose added with 10 μM of each test compound was added to each well in an amount of 0.25 ml and incubated at 37 ° C. for 22 minutes. The sample was collected and diluted 25 to 51 times, and then the insulin concentration was measured using an insulin concentration measurement kit (Rat Insulin [125I] Biotrak Assay System with Magnetic Separation; manufactured by Amersham Biosciences). The test compound was dissolved in 100% DMSO and added at a final concentration of 0.1%. The activity was expressed as a relative ratio when DMSO was 100%. The results are shown in Table 1.

上記のように、本発明の医薬の有効成分である化合物及び本発明化合物は、市販されているインスリン分泌促進剤であるグリベンクラミドと比較して、強いインスリン分泌促進作用を示した。

As described above, the compound which is an active ingredient of the medicament of the present invention and the compound of the present invention exhibited a strong insulin secretion promoting action as compared with glibenclamide which is a commercially available insulin secretion promoter.

(2) Normal Mouse Oral Glucose Tolerance Test In this test, the test compound using normal mice was examined for the blood glucose increase inhibitory effect after glucose load, using commercially available nateglinide having an oral blood glucose increase inhibitory effect as a control compound. The test method is shown below.
ICR mice (male, 6 weeks old) preliminarily raised for 1 week were fasted for 18 to 20 hours and used as test animals. The test compound was dissolved in 0.5% methylcellulose and orally administered at 3 mg / kg (10 mg / kg for nateglinide) before glucose loading. The test compound was administered at the optimal timing for each test compound. The compound of the present invention was 10 minutes before the glucose load, and the reference compound nateglinide was 30 minutes before the glucose load. The blood glucose reduction rate (%) relative to the control group at 30 minutes after glucose load was measured. The results are shown in Table 2.

上記のように、本発明の医薬の有効成分である化合物及び本発明化合物は、市販されている経口血糖低下剤であるナテグリニドと比較して、より低い投与量であるにもかかわらず、糖負荷後の血糖上昇に対してより強い抑制作用を示した。

As described above, the compound which is an active ingredient of the medicament of the present invention and the compound of the present invention have a glucose load despite a lower dose compared with nateglinide which is a commercially available oral hypoglycemic agent. It showed a stronger inhibitory effect on the subsequent increase in blood glucose.

The compound of the present invention will be further described as follows.
In the present specification, “lower” means a linear or branched carbon chain having 1 to 6 carbon atoms unless otherwise specified. Accordingly, “lower alkyl” means linear or branched C ₁ -C ₆ alkyl, specifically, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert -Butyl, pentyl, neopentyl, hexyl and the like can be mentioned, and preferred are C ₁ -C ₃ alkyl, methyl, ethyl, propyl and isopropyl. “Lower alkenyl” is linear or branched C ₂ -C ₆ alkenyl, and specific examples include vinyl, allyl, butenyl and the like. “Lower alkynyl” is linear or branched C ₂ -C ₆ alkynyl, and specific examples thereof include propargyl and the like. “Lower alkylidene” is linear or branched C ₁ -C ₆ alkylidene, and specific examples thereof include methylidene, ethylidene, and propylidene.
“Halogen” is fluoro, chloro, bromo or iodo, preferably fluoro, chloro or bromo.

  “Cyclic amino” has at least one nitrogen atom and further has one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and having 3 to 8 ring members A monovalent group of a non-aromatic cyclic amine means a group in which at least one nitrogen atom has a bond. In addition, the sulfur atom on the ring of the cyclic amino may be oxidized. Specific examples include monovalent groups such as azetidine, pyrrolidine, piperidine, azepan, azocan, piperazine, homopiperazine, morpholine, oxazepan, thiomorpholine, and thiazepan. These rings may have an unsaturated bond in a part of the ring, such as dihydropyrrole, tetrahydropyridine, tetrahydroazepine, imidazolidine, oxazolidine, dihydrooxazine, thiazolidine, dihydrothiazine and the like. These rings may be condensed with cycloalkyl such as decahydroquinoline and decahydroisoquinoline. These rings may be condensed with phenyl, such as indoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline and the like. These rings may be condensed with other cyclic amino groups such as octahydroimidazo [1,5-a] pyrazine, octahydro [1,2-a] pyrazine and the like. These rings are 2,3,4,9-tetrahydro-1H-b-carboline, 4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine, 4,5,6 , 7-tetrahydro-2H-pyrazolo [4,3-c] pyridine, 5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine, etc. Good. These rings are also 1,3,8-triazaspiro [4.5] decane, 1-oxa-8-azaspiro [4.5] decane, 1,4-dioxa-8-azaspiro [4.5] decane, 2,4-dioxa. It may be spiro-condensed with a non-aromatic heterocycle such as -9-azaspiro [5.5] undecane and 2,8-diazaspiro [4.5] decane. These rings may be a bridged cyclic amino group such as 2,5-diazabicyclo [2.2.1] heptane, 2,5-diazabicyclo [2.2.2] octane.

“Cycloalkyl” means a carbocyclic ring having 3 to 8 ring members, which may partially have an unsaturated bond. Specific examples include cyclopropyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclobutenyl, cyclohexenyl, cyclooctadienyl and the like. These rings may be condensed with phenyl.
“Aromatic heterocycle” means a monovalent group of an aromatic heterocycle having 5 to 6 ring members and containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Specific examples include monovalent groups such as pyrrole, pyridine, pyrazole, imidazole, pyridazine, pyrimidine, pyrazine, triazole, triazine, tetrazole, furan, thiophene, oxazole, thiazole, oxadiazole, and thiadiazole. These rings may be condensed with a phenyl ring such as indole, indazole and quinoline, or may be partially hydrogenated such as tetrahydropyridine, tetrahydroazepine, dihydropyridine and indoline.
“Non-aromatic heterocycle” is a saturated heterocycle having 5 to 6 ring members containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and optionally oxidized sulfur. Means a valent group. Specifically, for example, in addition to the cyclic amino, a monovalent group in which an atom other than the nitrogen atom of the cyclic amino has a bond, tetrahydrofuran, tetrahydropyran, tetrahydrothiofuran, tetrahydrothiopyran, dioxolane, 1,3-dioxane And monovalent groups such as 1,4-dioxane, and these rings may be bridged such as 1-azabicyclo [2.2.1] heptane and quinuclidine.
The “bridged cyclic amino” means a monovalent group of a ring in which two non-adjacent carbon atoms constituting the cyclic amino ring are bridged with methylene, ethylene or trimethylene.

  In the present specification, the permissible substituents of the words “which may be substituted” and “substituted” may be any substituents which are usually used as a substituent of each group. One or more of these substituents may be present in each group.

The R ¹ 'phenyl substituted with at least one halogen. Incidentally, the phenyl is further substituent may have. "" At least phenyl substituted with one halogen "in, and, for R ¹ "Each optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl", R ² "optionally substituted cyclic amino", R ²¹ and R ²² optionally substituted "cycloalkyl , Phenyl, aromatic heterocycle, and non-aromatic heterocycle ”include groups represented by the following (a) to (h). “R ^Z ” is substituted with —OH, —O-lower alkyl, —OCO-lower alkyl, carboxyl, —CO ₂ -lower alkyl, —CO-lower alkyl, one or two lower alkyls. One selected from the group consisting of optionally substituted carbamoyl, cyano, optionally substituted with one or two lower alkyls, phenyl, aromatic heterocycle, cycloalkyl, non-aromatic heterocycle, and halogen The lower alkyl which may be substituted by the above groups is shown.
(A) halogen;
^{(B) -OH, -OR Z,} -O- ^{phenyl, -OCO-R Z, -OCONH-} R Z, oxo (= O);
(C) —SH, —SR ^Z , —S-phenyl, —S-aromatic heterocycle, —SO—R ^Z , —SO-phenyl, —SO-aromatic heterocycle, —SO ₃ H, —SO ₂ -R ^Z , -SO ₂ -phenyl (this phenyl may be substituted with lower alkyl), -SO ₂ -aromatic heterocycle (this aromatic heterocycle may be substituted with lower alkyl) ), Sulfamoyl optionally substituted by one or two R ^Z ;
(D) 1 or 2 R ^Z amino optionally substituted, -NHCO-R ^Z, -NHCO- _{^{phenyl, -NHCO 2 -R Z, -NHCONH 2}} , -NHCONH-R Z, -NHSO 2 -R ^Z , -NHSO ₂ -phenyl (this phenyl may be substituted with lower alkyl), -NHSO ₂ NH ₂ , nitro;
(E) -CHO, -CO-R Z, -CO 2 H, -CO 2 -R Z, 1 or 2 carbamoyl optionally substituted with R ^Z, -CO- cyclic amino (this cyclic amino may Optionally substituted with -OH or oxo), -COCO-R ^Z , cyano;
(F) —OH, —O-lower alkyl, oxo, —S-lower alkyl, amino optionally substituted with one or two lower alkyls, cyclic amino, —CO ₂ H, one or two R ^Z in optionally substituted carbamoyl, halogen and one or more phenyl or cycloalkyl each optionally substituted with a group selected from the group consisting of R ^Z;
(G) —OH, —O-lower alkyl, oxo, —S-lower alkyl, amino optionally substituted with one or two lower alkyls, cyclic amino, —CO ₂ H, one or two R ^An aromatic or non-aromatic heterocyclic ring each optionally substituted with one or more groups selected from the group consisting of carbamoyl, halogen and R ^Z optionally substituted with ^Z ;
(H) Lower alkyl, lower alkenyl, or lower alkylidene, each of which may be substituted with one or more groups selected from the substituents shown in the above (a) to (g).
In addition, the substituents allowed in “lower alkyl, lower alkenyl, lower alkynyl, —O-lower alkyl” which may be substituted for R ²¹ and R ²² are shown in the above (a) to (g). Groups.

  The compound of the present invention represented by the formula (I) may contain an asymmetric carbon atom depending on the type of substituent, and optical isomers based on this may exist. The present invention includes all of these optical isomers and isolated ones. In addition, the compounds of the present invention may have tautomers, but the present invention includes a mixture or a mixture of these isomers. Further, the present invention includes a label, that is, a compound in which one or more atoms of the compound of the present invention are substituted with a radioactive isotope or a non-radioactive isotope.

  Further, the compound of the present invention may form a salt, and such a salt is included in the present invention as long as it is pharmaceutically acceptable. Specifically, addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid Acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid and other addition salts with organic acids, sodium, potassium, Examples include addition salts with inorganic bases containing metals such as calcium and magnesium, addition salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine and ornithine, and ammonium salts. Furthermore, the present invention also includes substances having various hydrates, solvates and crystal polymorphs of the compound of the present invention and pharmaceutically acceptable salts thereof. The present invention includes all compounds that are metabolized in vivo and converted to the compound represented by the formula (I) or a salt thereof, so-called prodrugs. Examples of the group that forms the prodrug of the present invention include those described in Prog. Med. 5: 2157-2161 (1985), Yodogawa Shoten 1990, “Development of Drugs”, Volume 7, Molecular Design pages 163-198. Group described in (1).

  The compound of the present invention and a pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods using characteristics based on the basic skeleton or the type of substituent. A typical production method is illustrated below. Moreover, it can also manufacture according to description of the reference example and Example which are mentioned later, or according to it. Depending on the type of functional group, it may be effective in terms of production technology to replace the functional group with a suitable protecting group at the raw material or intermediate stage, that is, a group that can be easily converted to the functional group. is there. Thereafter, the protecting group is removed as necessary to obtain the desired compound. Examples of such a functional group include a hydroxyl group, a carboxyl group, an amino group, and the like. Examples of the protective group include those described in “Protective Groups in Organic Synthesis (third edition)” by Greene and Wuts. Can be used as appropriate according to these reaction conditions.

（式中、環A、R¹及びR²は前述の意味を、YはO又はSを、Zは脱離基を示す。以下同様。）
本製法は式（1a）で示される脱離基を有する芳香環縮合ピリミジン誘導体に対し、式（1b）で示されるアミン誘導体を作用させ、一般式（Ｉ）で示される本発明化合物を製造する方法である。
化合物（1a）におけるZで示される脱離基としては、反応条件下において化合物（1b）のアミノ基の水素原子と共にHZの形で脱離しうる基を意味し、例えばフルオロ、クロロ、ブロモ、ヨード等のハロゲン、メタンスルホニルオキシのような低級アルキルスルホニルオキシ基、トリフルオロメタンスルホニルオキシのようなトリハロゲノメタンスルホニルオキシ基、ベンゼンスルホニルオキシ、ｐ−トルエンスルホニルオキシのようなアリールスルホニルオキシ基が挙げられる。

(In the formula, ring A, R ¹ and R ² have the above-mentioned meanings, Y represents O or S, Z represents a leaving group, and so on.)
In this production method, an amine derivative represented by the formula (1b) is allowed to act on an aromatic ring condensed pyrimidine derivative having a leaving group represented by the formula (1a) to produce the compound of the present invention represented by the general formula (I). Is the method.
The leaving group represented by Z in the compound (1a) means a group that can be removed in the form of HZ together with the hydrogen atom of the amino group of the compound (1b) under the reaction conditions. For example, fluoro, chloro, bromo, iodo And halogen, a lower alkylsulfonyloxy group such as methanesulfonyloxy, a trihalogenomethanesulfonyloxy group such as trifluoromethanesulfonyloxy, an arylsulfonyloxy group such as benzenesulfonyloxy and p-toluenesulfonyloxy.

The reaction between compound (1a) and compound (1b) is carried out under normal pressure or pressure, in the absence of a solvent or in a suitable solvent.
Specific examples of the solvent include aromatic hydrocarbons such as toluene and xylene; ketones such as methyl ethyl ketone and methyl isobutyl ketone; ethers such as ether, tetrahydrofuran (THF), dioxane and diglyme; methanol (MeOH), ethanol ( EtOH), alcohols such as 2-propanol (iPrOH); acetonitrile, dimethylformamide (DMF), 1,3-dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide (DMSO), water or a mixed solvent thereof Can be mentioned. This reaction is preferably performed in the presence of a base. Specific examples of the base include alkali carbonates such as sodium carbonate and potassium carbonate, alkali hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, triethylamine, diisopropylethylamine and the like. Although a secondary amine etc. are mentioned, it can serve also with the excess amount of a compound (1b). While the reaction temperature varies depending on the kind of raw material compound, reaction conditions and the like, it is generally about 20 ° C to about 180 ° C, preferably about 60 ° C to about 130 ° C.

Compound (1a) can be synthesized, for example, by halogenating or sulfonylating a pyrimidinone or pyrimidinethione derivative represented by formula (1c) according to a conventional method.
The halogenation in this reaction is carried out, for example, by reacting compound (1c) with a halogenating agent such as phosphorus oxychloride or phosphorus tribromide. The sulfonylation is performed by, for example, reacting the compound (1c) when Y is an oxygen atom with a sulfonylating agent such as methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride and the like. Done.

Compound (1c) can be obtained by known methods such as J. Am. Chem. Soc., 74, 842, (1952), Chem. Ber., 95, 937, (1962), or J. Org. Chem., 29, 2887, (1964) or a method analogous thereto. Compound (1b) is commercially available or can be synthesized by a known method.
In addition, some of the compounds of the present invention may be produced by using the above-described production methods, the methods described in the Examples, methods obvious to those skilled in the art, or the compounds of the present invention produced based on these modified methods. It can also be produced by subjecting it to a process that can be usually employed by those skilled in the art, such as oxidation, acylation, substitution reaction, oxidation, reduction, hydrolysis and the like.

The compound of the present invention thus produced is isolated or purified as it is in the free state or after being subjected to salt formation treatment by a known method. Isolation / purification is performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography.
Further, when the compound of the present invention has an asymmetric carbon, an optical isomer exists. These optical isomers can be resolved by a conventional method such as fractional crystallization by recrystallizing an appropriate salt or column chromatography. An optically active compound can also be produced by using an appropriate optically active raw material.

The medicament of the present invention can be prepared by a commonly used method using one or more of the compounds of the present invention and a pharmaceutical carrier, excipient, and other additives that are usually used for formulation. Administration is any of oral administration using tablets, pills, capsules, granules, powders, liquids, injections such as intravenous injection and intramuscular injection, or parenteral administration using suppositories, nasal, transmucosal, transdermal, etc. It may be a form.
As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, one or more active substances are at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminum metasilicate. Mixed with magnesium acid etc. The composition contains additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium calcium glycolate, a stabilizer, a solubilizing agent and the like according to a conventional method. May be. If necessary, tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, etc., or a gastric or enteric film.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert diluents such as purified water. , Ethanol (EtOH). In addition to the inert diluent, the composition may contain adjuvants such as wetting agents and suspending agents, sweeteners, flavors, fragrances and preservatives.
Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of the aqueous solution and suspension include distilled water for injection and physiological saline. Non-aqueous solutions and suspensions include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as EtOH, polysorbate 80 (Pharmacopeia name), and the like. Such a composition may further contain auxiliary agents such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving it in sterile water or a sterile solvent for injection before use.

  Usually, in the case of oral administration, the daily dose is about 0.0001 to 50 mg / kg per body weight, preferably about 0.001 to 10 mg / kg, more preferably 0.01 to 1 mg / kg, This is administered once or divided into 2 to 4 times. In the case of intravenous administration, the daily dose is about 0.0001 to 1 mg / kg, preferably about 0.001 to 0.1 mg / kg per body weight, and is administered once a day or divided into multiple times. The dosage is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.

  EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not restrict | limited at all by these Examples. In addition, the raw material compound used in an Example includes a novel substance, The manufacturing method from the well-known thing of such a raw material compound is demonstrated as a reference example.

Reference example 1
A solution of 4-chloro-2,5-difluorobenzonitrile in chloroform-EtOH is saturated with hydrogen chloride gas, stirred at room temperature for 16 hours, and concentrated to obtain a mixture of imidate, ammonium carbonate, and EtOH at room temperature. Was stirred for 3 days to obtain 4-chloro-2,5-difluorobenzenecarboxamidine.

In the same manner as in Reference Example 1, the compounds shown in Table 3 below were produced. The symbols in the table have the following meanings (the same applies hereinafter).
Rf: Reference example number.
Data: Physical data (MS: FAB-MS (M + H) ⁺ , MM: FAB-MS (M) ⁺ , MN: FAB-MS (MH) ⁻ , ME: ES-MS (M + H) ⁺ , MF: ES-MS (M) ⁺ , MG: ES-MS (M) ⁻ , MH: ES-MS (MH) ⁻ , MI: EI-MS (M + H) ⁺ , MJ: EI-MS (M ) ⁺ , MA: APCI-MS (M + H) ⁺ ).
Structure: Chemical structural formula.
R, R ¹ , R ² : substituents in the general formula (Me: methyl, Et: ethyl, cPen: cyclopentyl, cHex: cyclohexyl, pyrr: pyrrolidin-1-yl, pipe: piperidin-1-yl, hPy: 1 , 2,3,6-Tetrahydropyridin-1-yl, azep: azepan-1-yl, pipea: piperazin-1-yl, mor: morpholin-4-yl, hpipa: homopiperazin-1-yl, fur: furyl , Py: pyridyl, Pyox: 1-oxide pyridyl, tmor: thiomorpholin-4-yl, Ph: phenyl, Ms: methanesulfonyl, Boc: tert-butyloxycarbonyl, Ac: acetyl, di: di, tri: tri. The number before the substituent indicates the substitution position, and thus 4- (4-Py) -pipa, for example, indicates 4-pyridin-4-ylpiperazin-1-yl).

Reference example 2
2-Chloropyridine-4-carboxamidine was obtained by stirring a mixture of 2-chloroisonicotinonitrile, trimethylaluminum (1.01 M hexane solution), ammonium chloride and toluene with heating under reflux for 14 hours.
ME: 156

Reference example 3
By stirring a mixture of methyl 2,5-dichlorothiophene-3-carboxylate, trimethylaluminum (1.01 M hexane solution), ammonium chloride, and toluene for 3 days at reflux, 2,5-dichlorothiophene-3-carboxamidine was obtained. Obtained.
MF: 196

Reference example 4
Stir a mixture of 4-chloro-2,5-difluorobenzenecarboxamidine, ethyl 4-oxotetrahydrothiophene-3-carboxylate, sodium methoxide, MeOH for 19 hours at room temperature and then for 5 hours at 60 ° C. Gave 2- (4-chloro-2,5-difluorophenyl) -5,7-dihydrothieno [3,4-d] pyrimidin-4 (1H) -one.

  In the same manner as in Reference Example 4, the compounds shown in Table 4 to Table 5 below were produced.

Reference Example 5
tert-butyl 2- (4-chloro-2,5-difluorophenyl) -4-oxo-3,5,6,7-tetrahydro-4H-pyrrolo [3,4-d] pyrimidine-6-carboxylate, chloroform To the mixture of MeOH, 4M hydrochloric acid (HCl) -ethyl acetate (EtOAc) solution was added and stirred at room temperature for 5 hours to give 2- (4-chloro-2,5-difluorophenyl) -3,5,6, 7-tetrahydro-4H-pyrrolo [3,4-d] pyrimidin-4-one hydrochloride was obtained.
MS: 284

Reference Example 6
Stir a mixture of 2- (4-chloro-2,5-difluorophenyl) -5,7-dihydrothieno [3,4-d] pyrimidin-4 (1H) -one and phosphorus oxychloride at 90 ° C for 4 hours Gave 4-chloro-2- (4-chloro-2,5-difluorophenyl) -5,7-dihydrothieno [3,4-d] pyrimidine.

  In the same manner as in Reference Example 6, the compounds shown in Tables 6 to 7 below were produced.

Reference Example 7
Of 2- (4-chloro-2,5-difluorophenyl) -3,5,6,7-tetrahydro-4H-pyrrolo [3,4-d] pyrimidin-4-one hydrochloride, triethylamine, and methanesulfonyl chloride By stirring the methylene chloride solution at room temperature for 3 hours, 2- (4-chloro-2,5-difluorophenyl) -6- (methylsulfonyl) -6,7-dihydro-5H-pyrrolo [3,4-d Pyrimidin-4-yl methanesulfonate was obtained.

  In the same manner as in Reference Example 7, the compounds shown in Table 8 below were produced.

Reference Example 8
Stir a mixture of 4-chloro-2- (4-chloro-2,5-difluorophenyl) -5,7-dihydrothieno [3,4-d] pyrimidine, m-chloroperbenzoic acid, chloroform for 1 hour at room temperature This gave 4-chloro-2- (4-chloro-2,5-difluorophenyl) -5,7-dihydrothieno [3,4-d] pyrimidine-6,6-dioxide.

  In the same manner as in Reference Example 8, the compounds shown in Table 9 below were produced.

Reference Example 9
To a mixture of 1-benzyl-4-methyleneazepane hydrochloride and THF-water, add a solution of N-methylmorpholine-N-oxide and osmium tetroxide in tert-butanol and stir at room temperature for 24 hours, then 4M HCl- Treatment with EtOAc solution gave 1-benzyl-4- (hydroxymethyl) azepan-4-ol hydrochloride. To the obtained 1-benzyl-4- (hydroxymethyl) azepan-4-ol hydrochloride in EtOH solution, 10% palladium-supported activated carbon was added, and the mixture was stirred at room temperature for 6 hours in a hydrogen atmosphere to give 4- (hydroxymethyl) azepane. -4-ol hydrochloride was obtained.
MS: 146

Reference Example 10
Sodium hydride and 1-benzylazepan-3-one were added to a THF solution of ethyl diethoxyphosphorylacetate under ice-cooling, and the mixture was stirred at room temperature for 2 hours (1-benzylazepan-3-ylidene). A stereoisomer mixture was obtained. The obtained stereoisomeric mixture of (1-benzylazepan-3-ylidene) acetate was treated with 4M HCl-EtOAc solution, EtOH and 10% palladium on activated carbon were added, and the mixture was added under hydrogen atmosphere at room temperature for 15 hours. Stirring gave ethyl azepan-3-yl acetate hydrochloride.
MS: 186

Reference Example 11
A mixture of 1-tert-butoxycarbonylpiperidin-4-ol, sodium hydride, DMF is stirred at room temperature for 5 minutes, then 2-chloro-N, N-dimethylethylamine is added, and further stirred at room temperature for 30 minutes. -[(1-tert-Butoxycarbonylpiperidin-4-yl) oxy] -N, N-dimethylethylamine was obtained. The obtained mixture of 2-[(1-tert-butoxycarbonylpiperidin-4-yl) oxy] -N, N-dimethylethylamine and 4M HCl-dioxane solution was stirred at room temperature for 7 hours, and N, N-dimethyl -2- (Piperidin-4-yloxy) ethylamine dihydrochloride was obtained.
MS: 273

Reference Example 12
A mixture of 1-tert-butoxycarbonylpiperidin-4-ol, triethylamine, benzenesulfonyl chloride, and methylene chloride was stirred at room temperature for 2 days to obtain 1-tert-butoxycarbonylpiperidin-4-ylbenzenesulfonate. A mixture of the obtained 1-tert-butoxycarbonylpiperidin-4-ylbenzenesulfonate, diethyl malonate, 20% sodium ethoxide-EtOH solution, and EtOH was stirred with heating under reflux for 22 hours, [1- (tert- Butoxycarbonyl) piperidin-4-yl] diethyl malonate was obtained. The resulting mixture of diethyl [1- (tert-butoxycarbonyl) piperidin-4-yl] malonate, lithium borohydride, toluene, and THF was stirred at 60 ° C. for 18 hours to give 2- (1-tert- Butoxycarbonylpiperidin-4-yl) propane-1,3-diol was obtained. The resulting mixture of 2- (1-tert-butoxycarbonylpiperidin-4-yl) propane-1,3-diol, 4M HCl-dioxane solution, and MeOH was stirred at room temperature for 1 hour to give 2-piperidine-4 -Ilpropane-1,3-diol hydrochloride was obtained.
MS: 160

Reference Example 13
A mixture of (1-tert-butoxycarbonylpiperidine-4,4-diyl) dimethanol, 4M HCl-dioxane solution, and MeOH was stirred at room temperature for 2 hours to obtain piperidine-4,4-diyldimethanol hydrochloride. .
MS: 146

Reference Example 14
A mixture of 1-tert-butoxycarbonyl-4- (3-hydroxypropyl) piperidin-4-ol and 4M HCl-dioxane solution was stirred at room temperature for 3.5 hours to give 4- (3-hydroxypropyl) piperidin-4- All hydrochloride was obtained.
MS: 160

Reference Example 15
A mixture of 1-tert-butoxycarbonylpiperidin-4-one and N, N-dimethylformamide dimethyl acetal was stirred with heating under reflux for 6 hours to give 1-tert-butoxycarbonyl-3-[(dimethylamino) methylene] piperidine. -4-one was obtained. The resulting mixture of 1-tert-butoxycarbonyl-3-[(dimethylamino) methylene] piperidin-4-one, 2-hydrazinoethanol, and MeOH was stirred with heating under reflux for 2 hours to give 2- (5- tert-Butoxycarbonyl-4,5,6,7-tetrahydro-2H-pyrazolo [4,3-c] pyridin-2-yl) ethanol and 2- (5-tert-butoxycarbonyl-4,5,6,7 A mixture of -tetrahydro-1H-pyrazolo [4,3-c] pyridin-1-yl) ethanol was obtained. The resulting mixture, 4M HCl-EtOAc solution, and EtOH mixture was stirred at room temperature for 2 hours and 2- (4,5,6,7-tetrahydro-2H-pyrazolo [4,3-c] pyridine-2 A mixture of -yl) ethanol dihydrochloride and 2- (4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridin-1-yl) ethanol dihydrochloride was obtained.
ME: 168

Reference Example 16
A mixture of ethyl (2E)-(1-benzyl-3-methylpiperidin-4-ylidene) acetate, 1-chloroethyl chloroformate, and 1,2-dichloroethane was stirred with heating under reflux for 30 minutes and concentrated under reduced pressure. The residue was dissolved in EtOH and stirred for 10 minutes with heating under reflux to obtain ethyl (2E)-(3-methylpiperidin-4-ylidene) acetate.
MS: 184

Reference Example 17
Mixture of 1-tert-butoxycarbonylpiperazine, 3-hydroxypropionic acid, 1-hydroxybenzotriazole (HOBt), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), and DMF at room temperature For 24 hours to give 3- (4-tert-butoxycarbonylpiperazin-1-yl) -3-oxopropan-1-ol. A mixture of the obtained 3- (4-tert-butoxycarbonylpiperazin-1-yl) -3-oxopropan-1-ol, 4M HCl-dioxane solution, and MeOH was stirred at room temperature for 16 hours. -3-Piperazin-1-ylpropan-1-ol hydrochloride was obtained.
MS: 159

Reference Example 18
A mixture of N- (2-nitrobenzenesulfonyl) ethylenediamine, 2-chloroethanesulfonyl chloride, triethylamine, methylene chloride was stirred at 0 ° C. for 3 hours, and N- (2-{[(2-chloroethyl) sulfonyl] amino} ethyl)- 2-Nitrobenzenesulfonamide was obtained. This was dissolved in acetonitrile, cesium carbonate and tetrabutylammonium iodide were added, and the mixture was stirred at 80 ° C. for 21 hours to give 5-[(2-nitrophenyl) sulfonyl] -1,2,5-thiadiazepane 1,1 -Dioxide was obtained. This was dissolved in acetonitrile, 4-methylbenzenethiol and potassium carbonate were added, and the mixture was stirred at 50 ° C. for 21 hours to obtain 1,2,5-thiadiazepane 1,1-dioxide.

Reference Example 19
A mixture of N- (2-nitrobenzenesulfonyl) ethylenediamine, 3-hydroxy-2,2-dimethylpropionic acid, EDCI, HOBt, methylene chloride and DMF was stirred at room temperature for 4 hours, and 3-hydroxy-2,2-dimethyl- N- (2-{[(2-nitrophenyl) sulfonyl] amino} ethyl) propanamide was obtained. A mixture of this, triphenylphosphine, diethylazodicarboxylate in toluene and THF was stirred at 0 ° C. for 15 hours, and then 6,6-dimethyl-1-[(2-nitrophenyl) sulfonyl] -1,4-diazepane. Obtained -5-one. A mixture of this product, 4-methylbenzenethiol, potassium carbonate, and acetonitrile was stirred at room temperature for 3 hours to obtain 6,6-dimethyl-1,4-diazepan-5-one.

Example 1
4-chloro-2- (4-chloro-2,5-difluorophenyl) -5,7-dihydrothieno [3,4-d] pyrimidine 6,6-dioxide 410 mg, (R) -3-methylpiperidine (R A mixture of 323 mg) -mandelate, 0.60 ml diisopropylethylamine and 10 ml acetonitrile was stirred at 70 ° C. for 2 hours. 20 ml of water was added to the reaction mixture, and the mixture was extracted with 20 ml of EtOAc. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 0.40 g of a solid. To this solid, 4 ml of EtOH, 8 ml of EtOAc, and 0.5 ml of 4M HCl-EtOAc solution were sequentially added and stirred at room temperature. The residue obtained after evaporation of the solvent under reduced pressure was added with 4 ml of EtOAc, and the precipitated white solid was collected by filtration, and (R) -2- (4-chloro-2,5-difluorophenyl) -4- (3-methyl Piperidin-1-yl) -5,7-dihydrothieno [3,4-d] pyrimidine-6,6-dioxide hydrochloride 188 mg was obtained.

Example 2
4- {1- [2- (4-Chloro-2,5-difluorophenyl) -6,7-dihydro-5H-cyclopenta [d] pyrimidin-4-yl] piperidin-4-yl} ethyl butanoate 37.04 g A mixture of 160 ml of 1M aqueous sodium hydroxide solution and 400 ml of THF-EtOH (1: 1) was stirred at room temperature for 4 hours. To the reaction mixture was added 160 ml of 1M aqueous hydrochloric acid and 700 ml of water, and the mixture was extracted twice with chloroform. The obtained organic phase was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained solid was dissolved in 300 ml of THF, 50 ml of 4M HCl-EtOAc solution was added, and the mixture was concentrated under reduced pressure to obtain a solid. This solid was recrystallized from water-acetonitrile to give 4- {1- [2- (4-chloro-2,5-difluorophenyl) -6,7-dihydro-5H-cyclopenta [d] pyrimidine-4- [Il] piperidin-4-yl} butanoic acid hydrochloride 25.35 g was obtained.

Example 3
{1- [2- (4-Chloro-2,5-difluorophenyl) -6,6-dioxo-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] piperidin-4-ylidene} acetic acid A mixture of ethyl 390 mg, 6M aqueous hydrochloric acid 10 ml, and THF 10 ml was stirred at 90 ° C. for 5.5 hours. After the solvent was distilled off under reduced pressure, the precipitated solid was recrystallized from water-acetonitrile to give {1- [2- (4-chloro-2,5-difluorophenyl) -6,6-dioxo-5,7- Dihydrothieno [3,4-d] pyrimidin-4-yl] piperidin-4-ylidene} acetic acid hydrochloride 126 mg was obtained.

Example 4
1-tert-Butoxycarbonyl-4- [2- (4-chloro-2,5-difluorophenyl) -5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] piperazine 503 mg, MeOH 2 ml A mixture of 6 ml of 4M HCl-dioxane solution was stirred at room temperature for 1 hour. After adding 15 ml of 1M aqueous sodium hydroxide and 2 ml of diethyl ether to the reaction mixture, the precipitate was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure. The obtained solid was dissolved in 5 ml of MeOH, 2 ml of 4M HCl-dioxane solution was added, and then the solvent was removed under reduced pressure. The obtained residue was washed with EtOH-EtOAc and then dried under reduced pressure to give 2- (4-chloro-2,5-difluorophenyl) -4-piperazin-1-yl-5,7-dihydrothieno [3, 423 mg of 4-d] pyrimidine dihydrochloride was obtained.

Example 5
2- (4-Chloro-2,5-difluorophenyl) -4- (piperazin-1-yl) -5,7-dihydrothieno [3,4-d] pyrimidine dihydrochloride 350 mg, hydroxyacetic acid 72 mg, triethylamine A mixture of 0.22 ml, HOBt 128 mg, EDCI 182 mg, and DMF 10 ml was stirred at room temperature for 17 hours. 100 ml of water was added to the reaction mixture, and the precipitate was collected by filtration, washed with water, and dried at 50 ° C. under reduced pressure. The obtained solid was dissolved in 15 ml of THF, 2 ml of 4M HCl-dioxane solution was added, and the mixture was concentrated under reduced pressure to obtain a solid. This solid was recrystallized from acetonitrile-ether to give 2- {4- [2- (4-chloro-2,5-difluorophenyl) -5,7-dihydrothieno [3,4-d] pyrimidine- 315 mg of 4-yl] piperazin-1-yl} -2-oxoethanol hydrochloride was obtained.

Example 6
2- (4-Chloro-2,5-difluorophenyl) -4- (piperazin-1-yl) -5,7-dihydrothieno [3,4-d] pyrimidine dihydrochloride 364 mg, diisopropylethylamine 0.71 ml, DMF To the 10 ml mixture, 0.08 ml of methanesulfonyl chloride was added and stirred at room temperature for 19 hours. 100 ml of water was added to the reaction mixture, and the precipitate was collected by filtration, washed with water, and dried at 50 ° C. under reduced pressure to obtain 329 mg of a light brown solid. This was dissolved in 15 ml of THF, and 2 ml of 4M HCl-dioxane solution was added. The residue obtained by distilling off the solvent under reduced pressure was recrystallized from acetonitrile-water-ether to give 2- (4-chloro-2,5-difluorophenyl) -4- [4- (methylsulfonyl) piperazine 314 mg of -1-yl] -5,7-dihydrothieno [3,4-d] pyrimidine hydrochloride was obtained.

Example 7
[1- (2-Cyclopentyl-6,6-dioxo-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl) piperidin-4-yl] acetic acid 246 mg, ammonium carbonate 75 mg, HOBt 0.11 g , EDCI 0.16 g and DMF 6 ml were stirred at room temperature for 3 days. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with EtOAc. The obtained organic phase was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain a foam. This was dissolved in THF, 4M HCl-dioxane solution was added and concentrated under reduced pressure. The residue was washed with ether to give [1- (2-cyclopentyl-6,6-dioxo-5,7-dihydrothieno [ 184 mg of 3,4-d] pyrimidin-4-yl) piperidin-4-yl] acetamide hydrochloride was obtained.

Example 8
1- [6,6-Dioxide-2- (2,4,5-trifluorophenyl) -5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] -1,4-diazepan-5- To a mixture of 500 mg ON and 5 ml DMSO was added 89 mg sodium thiomethoxide, and the mixture was stirred at room temperature for 1 hour. Thereafter, 21 mg of sodium thiomethoxide was added, and the mixture was stirred at room temperature for 30 minutes. 50 ml of water was added to the mixture, and the precipitate was collected by filtration, washed with water, and dried under reduced pressure. Separately, the filtrate was extracted with a mixed solvent of ethyl acetate and THF, and the obtained organic phase was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure and mixed with the previous solid. The mixture was purified by silica gel column chromatography (chloroform-MeOH) to give 1- {2- [2,5-difluoro-4- (methylthio) phenyl] -6,6-dioxide-5,7-dihydrothieno [ 352 mg of 3,4-d] pyrimidin-4-yl} -1,4-diazepan-5-one was obtained.

Example 9
1- [6,6-Dioxide-2- (2,4,5-trifluorophenyl) -5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] -1,4-diazepan-5- To a mixture of 300 mg of ON and 6 ml of DMSO were added 95 mg of potassium cyanide and 383 mg of 18-crown-6-ether, and the mixture was stirred at room temperature for 1 hour and then at 80 ° C. for 1.5 hours. 30 ml of water was added to the mixture, and the mixture was extracted with a mixed solvent of ethyl acetate and THF. The obtained organic phase was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain 49 mg of a solid. The obtained solid was washed with acetonitrile-diethyl ether to give 4- [6,6-dioxide-4- (5-oxo-1,4-diazepan-1-yl) -5,7-dihydrothieno [3, 39 mg of 4-d] pyrimidin-2-yl] -2,5-difluorobenzonitrile was obtained.

Example 10
3- {1- [2- (4-Chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] piperidin-4-yl } To a mixture of 547 mg of ethyl propionate, 5 ml of THF, and 5 ml of ethanol, 59 mg of lithium borohydride was added under ice cooling, and the mixture was stirred at room temperature for 18 hours and then stirred at 60 ° C. for 3 days. To the mixture under ice cooling, 20 ml of 1M hydrochloric acid was added dropwise, and after stirring at room temperature for 10 minutes, 50 ml of 1M aqueous sodium hydroxide solution was added. The precipitate was collected by filtration, washed with water, and dried under reduced pressure. The obtained solid was purified by silica gel column chromatography (chloroform-MeOH) to obtain 280 mg of a solid. This was dissolved in THF, 4M HCl-dioxane solution was added and concentrated under reduced pressure. The residue was recrystallized from acetonitrile-diethyl ether to give 3- {1- [2- (4-chloro-2, 256 mg of 5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] piperidin-4-yl} propan-1-ol hydrochloride was obtained.

Example 11
1- [2- (4-chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] piperidin-4-one 400 mg, A mixture of methylene chloride (10 ml), aminoethanol (65 μl) and acetic acid (2 drops) was stirred at room temperature for 1 hour, sodium triacetoxyborohydride (617 mg) was added, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with a mixed solvent of chloroform and THF. The obtained organic phase was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was dissolved in THF-MeOH, 4M HCl-dioxane solution was added and concentrated under reduced pressure. The residue was recrystallized with EtOH-acetonitrile to give 2-({1- [2- (4- Chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] piperidin-4-yl} amino) ethanol dihydrochloride 426 mg It was.

Example 12
8- [2- (4-Chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] -2,8-diazaspiro [4.5 ] To a mixture of decane dihydrochloride 200 mg and acetonitrile 10 ml, add potassium carbonate 263 mg, potassium iodide 6 mg, (2-bromoethoxy) (tert-butyl) dimethylsilane 89 μl, and stir at 60 ° C for 3 days did. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The obtained organic phase was washed successively with 10% aqueous citric acid solution, saturated aqueous sodium chloride solution, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 199 mg of a solid. To this, 5 ml of 4M HCl-dioxane solution and 2 ml of methanol were added and stirred at room temperature for 1 hour. After the mixture was concentrated under reduced pressure, the residue was recrystallized with EtOH-acetonitrile-diethyl ether to give 2- {8- [2- (4-chloro-2,5-difluorophenyl) -6,6-dioxide. 169 mg of -5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] -2,8-diazaspiro [4.5] dec-2-yl} ethanol dihydrochloride was obtained.

Example 13
(2Z) -3- {1- [2- (4-Chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] piperidine -4-yl} Acrylic acid 200 mg, THF 5 ml, 4-methylmorpholine 47 μl, at −10 to −15 ° C., 56 μl isobutyl chloroformate in 1 ml THF was added dropwise at that temperature. Stir for 50 minutes. Next, 25 mg of sodium borohydride was added, and the mixture was stirred at room temperature for 30 minutes. Ethanol (3 ml) was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. Water and 1M aqueous hydrochloric acid were added, and the mixture was stirred for 15 minutes. The mixture was adjusted to alkaline with 1M aqueous sodium hydroxide solution and extracted with EtOAc. The obtained organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain 108 mg of a solid. This was dissolved in THF, 4M HCl-dioxane solution was added and concentrated under reduced pressure, and the residue was recrystallized from acetonitrile-diethyl ether to give (2Z) -3- {1- [2- (4- Chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] piperidin-4-yl} prop-2-en-1-ol hydrochloric acid 62 mg of salt was obtained.

Example 14
2- (4-Chloro-2,5-difluorophenyl) -4- (2,3,6,7-tetrahydro-1H-azepin-1-yl) -5,7-dihydrothieno [3,4-d] pyrimidine A mixture of 6,6-dioxide 264 mg, osmium tetroxide (2.5 wt% in tBuOH; several drops), N-methylmorpholine N-oxide 75 mg, THF 6 ml, and water 3 ml was stirred at room temperature for 4.5 hours. A sodium thiosulfate aqueous solution was added to the reaction mixture, and the precipitate was collected by filtration, washed with 50 ml of water and 50 ml of EtOAc-hexane (1: 1), and then dried at 70 ° C. under reduced pressure to obtain 244 mg of a colorless solid. This was dissolved in THF and 4M HCl-dioxane solution was added. The residue obtained by distilling off the solvent under reduced pressure was washed with EtOH to give (4R, 5S) -1- [2- (4-chloro-2,5-difluorophenyl) -6,6-dioxide-5 264 mg of 7,7-dihydrothieno [3,4-d] pyrimidin-4-yl] azepan-4,5-diol hydrochloride was obtained.

Example 15
1- [2- (4-Chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] -1,4-diazepan-5 -A mixture of 321 mg ON and 10 ml of 5% aqueous sulfuric acid was stirred at 100 ° C for 27 hours. After distilling off the solvent under reduced pressure, 10 ml of dioxane, 10 ml of saturated aqueous sodium hydrogen carbonate, and 0.18 g of DIBOC were sequentially added to the resulting residue, followed by stirring at room temperature for 1 hour. The precipitated solid was filtered, and the filtrate was distilled off under reduced pressure. The residue was dissolved in chloroform, washed with 5% aqueous citric acid solution and water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. 4M HCl-dioxane solution was added to the residue and stirred, and then the solvent was distilled off under reduced pressure. Saturated aqueous sodium hydrogen carbonate was added thereto, washed with chloroform, 5% aqueous citric acid solution was added, extracted with chloroform, and washed with water. The solvent was distilled off under reduced pressure, the residue was dissolved in THF, 4M HCl-dioxane solution was added, and the precipitated solid was collected by filtration to give a colorless solid N- (2-aminoethyl) -N- [2- (4 -Chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] -β-alanine dihydrochloride 92 mg was obtained.

Example 16
2- {1- [2- (4-Chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] piperidin-4-yl } A mixture of 2.20 g of acetamide and 20 ml of phosphorus oxychloride was stirred at 100 ° C. for 30 minutes. Phosphorous oxychloride was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate and ethyl acetate were added to the residue, and the precipitated solid was collected by filtration, washed with water and EtOAc, and then dried at 70 ° C. under reduced pressure to obtain 1.69 g of a slightly brown solid. . This was dissolved in THF and MeOH, and 4M HCl-dioxane solution was added. The residue obtained by distilling off the solvent under reduced pressure was washed with acetonitrile to give a colorless solid {1- [2- (4-chloro-2,5-difluorophenyl) -6,6-dioxide-5,7 81 mg of -dihydrothieno [3,4-d] pyrimidin-4-yl] piperidin-4-yl} acetonitrile hydrochloride was obtained.

Example 17
1- [2- (4-chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] piperidin-4-ol 571 mg, A mixture of 0.30 g of 4-nitrophenyl chloroformate, 0.12 ml of pyridine, and 10 ml of methylene chloride was stirred at room temperature for 17 hours. Saturated aqueous ammonia chloride was added to the reaction mixture, extracted twice with chloroform, and washed with saturated brine. The obtained organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 1- [2- (4-chloro-2,5-difluorophenyl) -6,6-dioxide- 894 mg of 5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] piperidin-4-yl 4-nitrophenyl carbonate was obtained.
1- [2- (4-Chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] piperidin-4-yl 4-nitro A mixture of phenyl carbonate 300 mg, 2- (methylamino) ethanol 43 mg, and DMF 5 ml was stirred at room temperature for 19.5 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, extracted twice with chloroform, and washed with saturated brine. After drying the organic phase with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained yellow oily substance was dissolved in THF, 4M HCl-dioxane solution was added, and the mixture was concentrated under reduced pressure to obtain a solid. The solid was recrystallized from acetonitrile-ether to give colorless solid 1- [2- (4-chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d ] Pyrimidin-4-yl] piperidin-4-yl (2-hydroxyethyl) methylcarbamate hydrochloride 120 mg was obtained.

Example 18
1- [2- (4-chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] piperidin-4-one 230 mg, A mixture of ethyl-4-aminobutyrate hydrochloride 140 mg, acetic acid 0.1 ml, dichloroethane 5 ml, DMF 5 ml was stirred at room temperature for 1 hour, sodium triacetoxyborohydride 353 mg was added, and the mixture was stirred at room temperature for 19 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, extracted twice with chloroform, and washed with saturated brine. After drying the organic phase with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-MeOH), and ethyl 4-({1- [2- (4-chloro-2,5-difluorophenyl) -6,6-dioxide-5,7 -Dihydrothieno [3,4-d] pyrimidin-4-yl] piperidin-4-yl} amino) butanoate 128 mg, 1- {1- [2- (4-chloro-2,5-difluorophenyl) -6, 91 mg of 6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] piperidin-4-yl} pyrrolidin-2-one was obtained. By recrystallizing the latter from EtOH, colorless solid 1- {1- [2- (4-chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d ] Pyrimidin-4-yl] piperidin-4-yl} pyrrolidin-2-one 65 mg was obtained.

Example 19
2-({1- [2- (4-Chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] piperidine-4- Yl} amino) ethanol 254 mg, NaOMe 103 mg, diethyl carbonate 0.2 ml, MeOH 5 ml was stirred at 70 ° C. for 46 hours. Water was added to the reaction mixture, and the precipitate was collected by filtration, washed with water, and dried at 70 ° C. under reduced pressure to obtain 193 mg of a solid. The obtained solid was dissolved in THF and MeOH, 4M HCl-dioxane solution was added, and the mixture was concentrated under reduced pressure to obtain a solid. By recrystallizing this solid with EtOH-acetonitrile-ether, a pale yellow solid 3- {1- [2- (4-chloro-2,5-difluorophenyl) -6,6-dioxide-5, 7-Dihydrothieno [3,4-d] pyrimidin-4-yl] piperidin-4-yl} -1,3-oxazolidine-2-one hydrochloride 172 mg was obtained.

Example 20
2- (4-Chloro-2,5-difluorophenyl) -4-piperazin-1-yl-5,7-dihydrothieno [3,4-d] pyrimidine 6,6-dioxide dihydrochloride 208 mg, diisopropylethylamine 0.19 A mixture of ml, ethyl isocyanate 0.1 ml, and DMF 5 ml was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the precipitate was collected by filtration, washed with water, and dried at 70 ° C. under reduced pressure to obtain 193 mg of a colorless solid. The obtained solid was dissolved in THF, 4M HCl-dioxane solution was added, and the mixture was concentrated under reduced pressure to obtain a solid. This solid was recrystallized with EtOH-acetonitrile to give 4- [2- (4-chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3, 159 mg of 4-d] pyrimidin-4-yl] -N-ethylpiperazine-1-carboxamide hydrochloride was obtained.

Example 21
Trans-4-{[2- (4-Chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] amino} cyclohexanol 180 mg was dissolved in 5 ml of methylene chloride, 0.11 ml of DAST was added at −78 ° C. and stirred for 3 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, extracted twice with chloroform, and washed with saturated brine. After drying the organic phase with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-EtOAc) to give a colorless solid 137 mg. This was dissolved in THF, 4M HCl-dioxane solution was added, and the mixture was concentrated under reduced pressure.The residue was washed with EtOH to give colorless solid 2- (4-chloro-2,5-difluorophenyl) -N-cyclohexa 83 mg of -3-en-1-yl-5,7-dihydrothieno [3,4-d] pyrimidin-4-amine 6,6-dioxide hydrochloride was obtained.

Example 22
4-chloro-2- (4-chloro-2,5-difluorophenyl) -5,7-dihydrothieno [3,4-d] pyrimidine 6,6-dioxide 600 mg, 4- (3-hydroxypropyl) piperidine- A mixture of 367 mg of 4-ol hydrochloride, 0.90 ml of diisopropylethylamine and 10 ml of acetonitrile was stirred at 70 ° C. for 12 hours. 20 ml of water was added to the reaction mixture, and the mixture was extracted with 30 ml of chloroform. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the obtained residue, 10 ml of EtOH and 2 ml of 4M HCl-dioxane solution were successively added, and the solvent was distilled off under reduced pressure. EtOH and EtOAc were added, and the mixture was stirred with heating. After cooling, the precipitated solid was collected by filtration. Triethylamine was added to the filtrate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain 120 mg of an oily substance. To this, 10 ml of THF and 0.5 ml of 4M HCl-dioxane solution were successively added, and the solvent was distilled off under reduced pressure. The resulting residue was recrystallized from THF and diethyl ether to give acetic acid 3- {1- [2- (4-chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3 , 4-d] pyrimidin-4-yl] -4-hydroxypiperidin-4-yl} propyl hydrochloride 64 mg was obtained.

The compounds shown in Tables 10 to 31 below were produced by using the production methods described above and methods obvious to those skilled in the art or variations thereof. The table shows the structures and physical data of these example compounds. The symbols in the table have the following meanings (the same applies hereinafter).
Ex: Example number (when only a number is described in the Ex column, it indicates that the compound of the example number is a hydrochloride salt, and the slash (/) and “f” following the number are described. In the case, the compound of the example number indicates a free form.)

Tables 32 to 37 below show the NMR data of some example compounds. The symbols in the table have the following meanings.
NMR: NMR data (δ (ppm) of a peak in ¹ H-NMR using tetramethylsilane as an internal standard and DMSO-d ₆ as a measurement solvent unless otherwise specified).

Tables 38 to 39 below show the structures of other compounds of the invention. These compounds can be easily produced by using the production methods described above, the methods described in the examples, methods obvious to those skilled in the art, or variations thereof. The symbols in the table have the following meanings.
No: Compound number.

  The compound of the present invention exhibits excellent insulin secretion promoting action and blood glucose elevation inhibiting action. Therefore, the compound of the present invention is useful for the treatment and / or prevention of insulin-dependent diabetes (type 1 diabetes), non-insulin-dependent diabetes (type 2 diabetes), insulin resistance disease, obesity and the like based on these actions. It is.

Claims (15)

A condensed pyrimidine derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof.

[The symbols in the formula have the following meanings.
A:
A ring selected from the group consisting of group X ¹ , group X ² , group X ³ and group X ⁴ . The carbon atom constituting the ring may be substituted with one or more groups selected from the group consisting of lower alkyl, —O-lower alkyl, halogen, carboxyl, —CO ₂ -lower alkyl and carbamoyl. Good. Moreover, the sulfur atom which comprises this ring may be oxidized.
Group X ¹ :

A group consisting of
Group X ^2:

A group consisting of
Group X ^3:

A group consisting of
Group X ^4:

A group consisting of
-R ¹ :
A group selected from the following (1) to (3).
(1) Phenyl substituted with at least one halogen. This phenyl may further have a substituent.
(2) Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl each optionally substituted.
(3) Pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, or furyl substituted with at least one halogen. These rings may be substituted with one or more same or different halogens. These rings are bonded to the 2-position of the pyrimidine ring in formula (I) with the carbon atoms constituting these rings.
Provided that when A is a ring selected from group X ⁴ , -R ¹ represents phenyl substituted with at least three halogens.
-R ² :
A group represented by the formula (II) or a cyclic amino which may be substituted.

[The symbols in the formula have the following meanings.
-R ²¹ , -R ²² :
The same or different, -H, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, phenyl, aromatic heterocycle, non-aromatic heterocycle or -O-lower alkyl; Each of these groups may be substituted. ]
However, when A is a ring selected from Group X ² or Group X ³ , -R ² represents an optionally substituted cyclic amino.
However, 2- (2-fluorophenyl) -N, N-dimethyl-5,7-dihydrothieno [3,4-d] pyrimidin-4-amine and 2-cyclopropyl-4-piperazin-1-yl-5 , 7-Dihydrothieno [3,4-d] pyrimidine is excluded. ] A ring A is selected from the group X ^1, a compound according to claim 1. 3. A compound according to claim 2, wherein R < ¹ > is phenyl substituted with at least one halogen. 4. A compound according to claim 3, wherein R < ¹ > is phenyl substituted with at least 3 halogens. The compound of claim 4, wherein R ² is an optionally substituted cyclic amino. The compound according to claim 5, wherein R ² is an optionally substituted piperazine or an optionally substituted piperidine. The compound according to claim 2, wherein each R ¹ is optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. The compound according to claim 7, wherein each R ¹ is optionally substituted cyclobutyl or cyclopentyl. And R ² is is an optionally substituted cyclic amino, wherein The compound of claim 8. The compound according to claim 9, wherein R ² is an optionally substituted piperazine or an optionally substituted piperidine. 3- {4- [2- (4-Chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] piperazin-1-yl } Propanamide,
1- [2- (4-Chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] -4- (3-hydroxypropyl Piperidin-4-ol,
N-({1- [2- (4-Chloro-2,5-difluorophenyl-6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] piperidin-4-yl } Methyl) -2-hydroxyacetamide,
3- {1- [2- (4-Chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] piperidin-4-yl } Propanamide,
3-({1- [2- (4-Chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] piperidine-4- Il} amino) propan-1-ol,
3-({1- [2- (4-Chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl] piperidine-4- Yl} amino) propionic acid,
4- [1- (2-cyclopentyl-6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl) piperidin-4-yl] butyric acid,
4- [1- (2-cyclobutyl-6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl) piperidin-4-yl] butyric acid, and
4- {1- [2- (4-Chloro-2,5-difluorophenyl) -6,6-dioxide-5,7-dihydrothieno [3,4-d] pyrimidin-4-yl) piperidin-4-yl ] Butyric acid,
The compound according to claim 1, which is a compound selected from the group consisting of these pharmaceutically acceptable salts. A pharmaceutical composition comprising the compound according to claim 1 as an active ingredient. The pharmaceutical composition according to claim 12, which is a therapeutic agent for insulin-dependent diabetes (type 1 diabetes), non-insulin-dependent diabetes (type 2 diabetes), insulin resistance disease, or obesity. The pharmaceutical composition according to claim 12, which is an insulin secretagogue. The pharmaceutical composition according to claim 12, which is a blood sugar elevation inhibitor.